Intravesical Mucoadhesive Hydrogel Induces Chemoresistant Bladder Cancer Ferroptosis through Delivering Iron Oxide Nanoparticles in a Three-Tier Strategy

Abstract

Bladder cancer (BCa) is the most costly solid tumor owing to its high recurrence. Relapsed cancer is known to acquire chemoresistant features after standard intravesical chemotherapy. This cancer state is vulnerable to ferroptosis, which occurs when lipid peroxides generated by iron metabolism accumulate to lethal levels. Increasing the labile iron pool (LIP) by iron oxide nanoparticles (IONPs) promises to inhibit chemoresistant BCa (CRBCa), but systemically administered IONPs do not sufficiently accumulate at the tumor site. Therefore, their efficacy is weakened. Here, we present a three-tier delivery strategy through a mucoadhesive hydrogel platform conveying hyaluronic acid-coated IONPs (IONP−HA). When instilled, the hydrogel platform first adhered to the interface of the tumor surface, sustainably releasing IONP−HA. Subsequently, the tumor stiffness and interstitial fluid pressure were reduced by photothermal therapy, promoting IONP−HA diffusion into the deep cancer tissue. As CRBCa expressed high levels of CD44, the last delivery tier was achieved through antibody-mediated endocytosis to increase the LIP, ultimately inducing ferroptosis. This three-tiered strategy delivered the IONPs stepwise from anatomical to cellular levels and increased the iron content by up to 50-fold from that of systematic administration, which presents a potential regimen for CRBCa.

(Nano)platforms in bladder cancer therapy: Challenges and opportunities

“…The reason for using hydrogels is that IONPs cannot sufficiently accumulate at tumor site and in addition, increasing iron levels in IONPs promotes their efficacy in chemosensitivity via inducing ferroptosis. The IONPs were modified with HA and they were selectively internalized in bladder tumor cells overexpressing CD44 receptor via endocytosis 195 . As a proof for the statement that both functional and nonfunctional nanomaterials can use endocytosis for internalization in bladder tumor cells, a study reported methotrexate‐loaded magnetic nanostructures are probably internalized via receptor‐mediated endocytosis 196 .…”

“…The IONPs were modified with HA and they were selectively internalized in bladder tumor cells overexpressing CD44 receptor via endocytosis. 195 As a proof for the statement that both functional and nonfunctional nanomaterials can use endocytosis for internalization in bladder tumor cells, a study reported methotrexate‐loaded magnetic nanostructures are probably internalized via receptor‐mediated endocytosis. 196 Although studies have shown the potential of nanoparticles for internalizing into bladder tumor cells via endocytosis, 197 there are major gaps and limitations that should be addressed in future studies.…”

Designing Intelligent Nanomaterials to Achieve Highly Sensitive Diagnoses and Multimodality Therapy of Bladder Cancer

“…They have several advantages, including a good chemical stability, excellent biocompatibility, passive targeting ability, large specific surface area, good thermal stability, high drug loading, and so on. [130] PLZ4@SeD [84] DOX-PS [85] SeDs [87] Thiolated MSN NPs [131] PAMAM-modified MSNPs [132] FA-TMLs@MNPs-GNRs-DOX [135] LP-gel [148] PLL-P(LP-co-LC) [149] Ur-PDA NC [154] NG/HCPT [155] OEGMA-PTX@Ce6 [156] SS CB GB [157] PEG-PAMAM NPs [160] IONP-HA@Gel [168] KP372-1 [86] Cy3-labeled 293T-R-Fe@OA [174] RT HSA-MnO 2 -CQ [92] CDT AgNPs [125] CONPs [133] nZnO [134] IT IR775@Met@Lip [96] MPDIα W [97] 522NP [98] AB680@EMVs-aPDL1 [99] PGFCS [100] CWS-NP [145] CWS-Nano-CL [146] CWS-FPL [147] Fe 3 O 4 @Chl/Fe CNPs [137] GT siRNA@CS-HAD [102] UMND [103] HNTs/siRNA [104] CRISPR-Cas13a/liposome systems [105] siNrf GCD [164] KDM6A-mRNA NPs [106] SCNTs/si-circPRMT5 [143] PTT Fe 3 O 4 @PDA-VCA-FA SPs [67] HAPO-1048 [112] BBTD+GA/PEG-RGD [113] Cu 2-X Se [128] HA-IR780 NP…”

A comprehensive review on hydrogel materials in urology: Problems, methods, and new opportunities

“…Thanks to INOP labeling with hyaluronic acid, the uptake and binding of CD44 occurs, leading to an increase of the labile iron pool that results in ferroptosis of chemoresistant bladder cancer cells. The study conducted on a mouse model has shown that the developed platform providing local sustained high concentrations of IONP‐HA allows a reduction in tumor volume by about 40% compared to the control group 85 . A recent achievement of Afif Shafiq's team is the development of a second‐generation drug delivery system based on a hydrogel combination of Pluronic F127 and methacrylic acid for the controlled release of tolterodine tartrate.…”

“…The team of Zhongming Huang et al 84 Thermosensitive copolymer hydrogel of 3-caprolactone, The team of Ao Qi et al 85 Mucoadhesive hydrogel platform coated with hyaluronic acid (IONP-HA@Gel)…”